Anita L. Kozyrskyj

Antibiotic Use in Children Is Associated With Increased Risk of Asthma

BACKGROUND. Antibiotic exposure in early childhood is a possible contributor to the increasing asthma prevalence in industrialized countries. Although a number of published studies have tested this hypothesis, the results have been conflicting. OBJECTIVE. To explore the association between antibiotic exposure before 1 year of age and development of childhood asthma. METHODS. Using administrative data, birth cohorts from 1997 to 2003 were evaluated (N = 251817). Antibiotic exposure was determined for the first year of life. After the first 24 months of life, the incidence of asthma was determined in both those exposed and not exposed to antibiotics in the first 12 months of life. Cox proportional hazards models were used to adjust for potential confounders and determine the hazard ratios associated with antibiotic exposure for the development of asthma. RESULTS. Antibiotic exposure in the first year of life was associated with a small risk of developing asthma in early childhood after adjusting for gender, socioeconomic status at birth, urban or rural address at birth, birth weight, gestational age, delivery method, frequency of physician visits, hospital visit involving surgery, visits to an allergist, respirologist, or immunologist, congenital anomalies, and presence of otitis media, acute, or chronic bronchitis, and upper and lower respiratory tract infections during the first year of life. As the number of courses of antibiotics increased, this was associated with increased asthma risk, with the highest risk being in children who received >4 courses. All antibiotics were associated with an increased risk of developing asthma, with the exception of sulfonamides. CONCLUSIONS. This study provides evidence that the use of antibiotics in the first year of life is associated with a small risk of developing asthma, and this risk increases with the number of courses of antibiotics prescribed.

Asthma and genes encoding components of the vitamin D pathway

BackgroundGenetic variants at the vitamin D receptor (VDR) locus are associated with asthma and atopy. We hypothesized that polymorphisms in other genes of the vitamin D pathway are associated with asthma or atopy.MethodsEleven candidate genes were chosen for this study, five of which code for proteins in the vitamin D metabolism pathway (CYP27A1, CYP27B1, CYP2R1, CYP24A1, GC) and six that are known to be transcriptionally regulated by vitamin D (IL10, IL1RL1, CD28, CD86, IL8, SKIIP). For each gene, we selected a maximally informative set of common SNPs (tagSNPs) using the European-derived (CEU) HapMap dataset. A total of 87 SNPs were genotyped in a French-Canadian family sample ascertained through asthmatic probands (388 nuclear families, 1064 individuals) and evaluated using the Family Based Association Test (FBAT) program. We then sought to replicate the positive findings in four independent samples: two from Western Canada, one from Australia and one from the USA (CAMP).ResultsA number of SNPs in the IL10, CYP24A1, CYP2R1, IL1RL1 and CD86 genes were modestly associated with asthma and atopy (p < 0.05). Two-gene models testing for both main effects and the interaction were then performed using conditional logistic regression. Two-gene models implicating functional variants in the IL10 and VDR genes as well as in the IL10 and IL1RL1 genes were associated with asthma (p < 0.0002). In the replicate samples, SNPs in the IL10 and CYP24A1 genes were again modestly associated with asthma and atopy (p < 0.05). However, the SNPs or the orientation of the risk alleles were different between populations. A two-gene model involving IL10 and VDR was replicated in CAMP, but not in the other populations.ConclusionA number of genes involved in the vitamin D pathway demonstrate modest levels of association with asthma and atopy. Multilocus models testing genes in the same pathway are potentially more effective to evaluate the risk of asthma, but the effects are not uniform across populations.

Suicide and suicide attempts in children and adolescents in the child welfare system

Background: Few population studies have examined the psychiatric outcomes of children and adolescents in the child welfare system, and no studies have compared outcomes before and after entry into care. Our objective was to assess the relative rate (RR) of suicide, attempted suicide, admission to hospital and visits to physicians’ offices among children and adolescents in care compared with those not in care. We also examined these outcomes within the child welfare population before and after entry into care. Methods: We used population-level data to identify children and adolescents 5 to 17 years of age who were in care in Manitoba for the first time between Apr. 1, 1997, and Mar. 31, 2006, and a comparison cohort not in care. We compared the two cohorts to obtain RRs for the specified outcomes. We also determined RRs within the child welfare population relative to the same population two years before entry into care. Results: We identified 8279 children and adolescents in care for the first time and a comparison cohort of 353 050 children and adolescents not in care. Outcome rates were higher among those in care than in the comparison cohort for suicide (adjusted RR 3.54, 95% confidence interval [CI] 2.11–5.95), attempted suicide (adjusted RR 2.11, 95% CI 1.84–2.43) and all other outcomes. However, adjusted RRs for attempted suicide (RR 0.27, 95% CI 0.21–0.34), admissions to hospital and physician visits decreased after entry into care. Interpretation: Children and adolescents in care were at greater risk of suicide and attempting suicide than those who were not in care. Rates of suicide attempts and hospital admissions within this population were highest before entry into care and decreased thereafter.

Diagnosing asthma in children: what is the role for methacholine bronchoprovocation testing?

To determine whether measurement of airways responsiveness to methacholine can help physicians diagnose asthma in children.

Identifying Children with Persistent Asthma from Health Care Administrative Records

BACKGROUND Investigation into the origins of asthma is contingent on definitions of asthma, which can differentiate asthma from transient wheezing syndromes in children. OBJECTIVES This research was undertaken to develop a definition for asthma derived from health care administrative records, which would identify children with persistent asthma. PATIENTS AND METHODS Using population-based, health care administrative data, children with possible asthma were identified as having one or more physician visits or hospitalizations for asthma or bronchitis diagnoses from January 1995 to December 1995, or, in the absence of asthma-like diagnoses, one or more prescriptions for asthma prophylaxis drugs or ketotifen concomitant with a beta-agonist, or two or more prescriptions for beta-agonists. RESULTS The likelihood of persistent asthma, defined as repeated health care and prescription use for asthma from 1996 to 1998, was assessed for various asthma markers and risk factors in 29,198 children with possible asthma. Children with asthma prescription drugs or asthma health care use not limited to the winter season were three to six times more likely than children without these characteristics to have persistent asthma. The likelihood of persistent asthma was elevated to a substantial degree in the presence of both of these markers. CONCLUSIONS The inclusion of these measures in a diagnosis-based definition improves the ability to identify persistent asthma in children.

TLR4 Asp299Gly and Thr399Ile Polymorphisms: No Impact on Human Immune Responsiveness to LPS or Respiratory Syncytial Virus

Background A broad variety of natural environmental stimuli, genotypic influences and timing all contribute to expression of protective versus maladaptive immune responses and the resulting clinical outcomes in humans. The role of commonly co-segregating Toll-like receptor 4 (TLR4) non-synonymous single nucleotide polymorphisms Asp299Gly and Thr399Ile in this process remains highly controversial. Moreover, what differential impact these polymorphisms might have in at risk populations with respiratory dysfunction, such as current asthma or a history of infantile bronchiolitis, has never been examined. Here we determine the importance of these polymorphisms in modulating LPS and respiratory syncytial virus (RSV) - driven cytokine responses. We focus on both healthy children and those with clinically relevant respiratory dysfunction. Methodology To elucidate the impact of TLR4 Asp299Gly and Thr399Ile on cytokine production, we assessed multiple immune parameters in over 200 pediatric subjects aged 7–9. Genotyping was followed by quantification of pro- and anti-inflammatory cytokine responses by fresh peripheral blood mononuclear cells upon acute exposure to LPS or RSV. Principal Findings In contrast to early reports, neither SNP influenced immune responses evoked by LPS exposure or RSV infection, as measured by the intermediate phenotype of pro- and anti-inflammatory cytokine responses to these ubiquitous agents. There is no evidence of altered sensitivity in populations with “at risk” clinical phenotypes. Conclusions/Significance Genomic medicine seeks to inform clinical practice. Determination of the TLR4 Asp299Gly/Thr399Ile haplotype is of no clinical benefit in predicting the nature or intensity of cytokine production in children whether currently healthy or among specific at-risk groups characterized by prior infantile broncholitis or current asthma.

Altered epigenetic regulation and increasing severity of bronchial hyperresponsiveness in atopic asthmatic children

who failed their repeat milk OFC. Because this was a retrospective chart review of a clinical population rather than a designed research protocol, uncontrolled factors such as seasonality, patient maturity, and family/patient decisions of whether and when to repeat OFC likely had some impact. However, with the possible exception of those who have severe symptoms to their initial milk OFC, the circumstances of the initial failed OFC are poorly correlated with the outcomes of repeat OFCs. This suggests patients who have not had known reactions in the interim should be considered candidates for a repeat OFC, regardless of the circumstances of the initial OFC.

Characterizing early prescribers of newly marketed drugs in Canada: a population-based study

BackgroundThe diffusion of innovations model proposes that early adopters of innovation influence others. This study was undertaken to determine if early prescribers and users of newly marketed drugs had different sociodemographic and professional characteristics as compared to majority and late users and prescribers.MethodsAfter market availability in Manitoba, Canada, of celecoxib, alendronate, clopiodogrel and pantoprazole, time to first prescriptions was determined. Early, majority and late adopters of the new drug were characterized by this diffusion time. The prescription, health and prescriber records were compared across adopter categories. The likelihood of being an early or late prescriber or user of the new medications according to patient demographic characteristics, physician factors (specialty and place of training) and neighborhood income was determined with polytomous logistic regression.ResultsCelecoxib demonstrated a much more rapid uptake into routine use than the other drugs. More than 300 Manitoba physicians prescribed celecoxib within two weeks of market availability. Early prescribers of celecoxib were more likely than majority prescribers to be general practitioners (OR = 1.81, 95%CI: 1.40–2.35) and have hospital affiliations (OR = 1.35, 95%CI: 1.03–1.77). Early users of celecoxib were more likely than the majority to have arthritic conditions, have a high income and have paid out-of-pocket for their prescription. For alendronate, clopidogrel and pantoprazole, only prescription drug coverage predicted adopter category. Early prescribers of one new drug were not early prescribers of the other new drugs.ConclusionNo common group of patients or physicians who were early prescribers or users of all four medications was described.

Should Younger Siblings of Peanut-Allergic Children Be Assessed by an Allergist before Being Fed Peanut?

The objective of this study was to determine the risk of peanut allergy in siblings of peanut-allergic children. In 2005-2006, 560 households of children born in 1995 in the province of Manitoba, Canada, were surveyed. The index children (8-to 10-year-olds) were assessed by a pediatric allergist and had skin-prick testing and/or capRAST for peanut allergy. Surveys were completed by parents for siblings to determine the presence of peanut allergy. Of 560 surveys, 514 (92%) were completed. Twenty-nine (5.6%) index children were peanut allergic. Fifteen of 900 (1.7%) siblings had peanut allergy. Four of 47 (8.5%) were siblings of peanut-allergic children and 11 of 853 (1.3%) were siblings of non-peanut-allergic children. The risk of peanut allergy was markedly increased in siblings of a peanut-allergic child (odds ratio 6.72, 95% confidence interval 2.04-22.12). Siblings of peanut-allergic children are much more likely to be allergic to peanut. An allergy assessment by a qualified allergist should be routinely recommended before feeding peanut to these children.

Trends in Psychostimulant and Antidepressant Use by Children in 2 Canadian Provinces

Objective: We used population-based administrative prescription medication data to examine regional differences in psychostimulant and antidepressant (AD) use among children from 2 Canadian provinces: British Columbia (BC) and Manitoba (MB). Method: Using 1997 to 2003 prescription data, annual rates of psychostimulant and AD use were determined for children aged 19 years and under in both provinces. Further comparisons of rates were made according to sex, age group, and specific classes of dispensed medications. Results: During 1997 to 2003, psychostimulant use rose by 44.9% in MB and 13.3% in BC. Among male children, psychostimulant use increased by 40.2% in MB, compared with an increase of only 8.6% in BC. AD utilization was similar between provinces, with increases of 80% and 75% in MB and BC, respectively. In both provinces, AD use was highest among older children. Conclusions: Our observations of regional variation in psychotropic medication use potentially reflect provincial differences in drug benefit policies, disease prevalence, and (or) physician diagnosis and treatment.